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Controlled Endolysosomal Release of Agents by pH-responsive Polymer Blend Particles

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ABSTRACT

Purpose

A key step of delivering extracellular agents to its intracellular target is to escape from endosomal/lysosomal compartments, while minimizing the release of digestive enzymes that may compromise cellular functions. In this study, we examined the intracellular distribution of both fluorecent cargoes and enzymes by a particle delivery platform made from the controlled blending of poly(lactic-co-glycolic acid) (PLGA) and a random pH-sensitive copolymer.

Methods

We utilized both microscopic and biochemical methods to semi-quantitatively assess how the composition of blend particles affects the level of endosomal escape of cargos of various sizes and enzymes into the cytosolic space.

Results

We demonstrated that these polymeric particles enabled the controlled delivery of cargos into the cytosolic space that was more dependent on the cargo size and less on the composition of blend particles. Blend particles did not induce the rupture of endosomal/lysosomal compartments and released less than 20% of endosomal/lysosomal enzymes.

Conclusions

This study provides insight into understanding the efficacy and safety of a delivery system for intracellular delivery of biologics and drugs. Blend particles offer a potential platform to target intracellular compartments while potentially minimizing cellular toxicity.

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Abbreviations

PLGA:

Poly(lactic-co-glycolic acid)

PAA:

2-Propylacrylic acid

BMA:

Butyl methacrylate

DMAEMA:

2-(dimethylamino)ethyl methacrylate

AIBN:

2,2′-azobis(2-methylpropionitrile)

DCM:

Dichloromethane

PVA:

Polyvinyl alcohol

PS:

Polystyrene

PS-NH2:

Amine-end polystyrene particles

PS-COOH:

Carboxylate-modified polystyrene particles

DPBS:

Dulbecco’s phosphate buffered saline

AO:

Acridine orange

DAPI:

4′,6-diamidino-2-phenylindole

FITC:

Fluorescein isothiocyanate

NAG:

N-acetyl-β-D-glucosaminidase

NMR:

Nuclear magnetic resonance spectroscopy

GPC:

Gel permeation chromatography

DLS:

Dynamic light scattering

SEM:

Scanning electron microscope

MW:

Molecular weight

PDI:

Polydispersity index

LAMP-2:

Lysosomal associated membrane protein-2

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ACKNOWLEDGMENTS AND DISCLOSURES

The authors want to thank the Cell Analysis Facility in the Department of Immunology, the Keck Microscopy Facility, and the NanoTech User Facility (NTUF) in University of Washington. This study was funded by (AI088597) from the National Institutes of Health (NIH) and the NSF CAREER Award to H.S.

Author information

Author notes

  1. Kenny K. Tran

    Present address: Biogen Idec, 14 Cambridge Center, Cambridge, MA, 02142, USA

Authors and Affiliations

  1. Department of Biological Structure, University of Washington School of Medicine, Seattle, WA, 98195, USA

    Xi Zhan & Liguo Wang

  2. Department of Chemical Engineering, University of Washington, Seattle, WA, 98195, USA

    Kenny K. Tran

  3. Elsa Biologics, LLC, Box 25725, Seattle, WA, 98165, USA

    Hong Shen

Authors
  1. Xi Zhan
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  2. Kenny K. Tran
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  3. Liguo Wang
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Corresponding author

Correspondence to Hong Shen.

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Zhan, X., Tran, K.K., Wang, L. et al. Controlled Endolysosomal Release of Agents by pH-responsive Polymer Blend Particles. Pharm Res 32, 2280–2291 (2015). https://doi.org/10.1007/s11095-015-1619-0

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  • DOI: https://doi.org/10.1007/s11095-015-1619-0

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